The addition of the targeted angiogenesis inhibitor aflibercept (Zaltrap, Regeneron/Sanofi) to chemotherapy did not prolong overall survival in men with metastatic castration-resistant prostate cancer (CRPC), according to the phase 3 VENICE trial.
The results, published in the July issue of Lancet Oncology, are not that surprising. There have been at least 7 large phase 3 trials in which a targeted agent was added to chemotherapy with docetaxel in CRPC. All have been unsuccessful.
"Despite a substantial expenditure in terms of patients' time and financial resources, none of these trials have shown an improvement in survival beyond that achieved with docetaxel alone," write Michael Galsky, MD, and William Oh, MD, from the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, in an accompanying comment.
The study authors estimate that, in total, the 8 negative trials recruited close to 7800 men and cost close to US$1 billion.
"Furthermore, most experimental combination regimens tested led to increased toxicity compared with docetaxel alone," Drs. Galsky and Oh add.
Does Not Warrant Further Investigation
One of the previous trials — the CALGB 90401 study (J Clin Oncol. 2012;30:1534-1540) — investigated bevacizumab (Avastin, Genentech/Roche) in 1050 men with metastatic CRPC.
Bevacizumab and aflibercept are both angiogenesis inhibitors that target vascular endothelial growth factor, although by slightly different mechanisms. Both are marketed for use in the treatment of colorectal cancer and macular degeneration; bevacizumab is also marketed for use in a number of other cancers.
Results from the VENICE and CALGB 90401 trials had "striking similarities," Drs. Galsky and Oh note. Neither trial showed an improvement in survival, and both showed an increase in fatal treatment-related adverse events with the experimental combinations. In both trials, the fatal events were mainly infectious, rather than vascular, they add.
There were a few differences in the secondary end points of the 2 trials. For instance, improvement in progression-free survival was substantial with bevacizumab, but not with aflibercept.
This could indicate some differences in the clinical activity of the 2 drugs in CRPC; however, the fact there was more toxicity when the drugs were combined with docetaxel and that neither improved survival "confirms that this therapeutic approach does not warrant further investigation," Drs. Galsky and Oh write.
A similar conclusion was reached by Tomasz Beer, MD, FACP, professor of medicine at the Oregon Health & Science University in Portland, who reviewed prostate cancer research in a 'highlights of the day' session at the recent American Society of Clinical Oncology annual meeting. He noted that the VENICE trial is the eighth trial in which a targeted agent added to docetaxel has failed.
Table. Negative Phase 3 Trials in Which a Targeted Drug Was Added to Docetaxel
| Trial | Therapy | Result |
| ASCENT II | Calcitriol | Poorer survival in experimental group |
| VITAL II | GVAX vaccine | Poorer survival in experimental group |
| SWOG SO421 | Atrasentan | No difference in progression-free survival or survival |
| ENTHUSE | Zibotentan | No significant difference in survival |
| MAINSAIL | Lenalidomide | No survival difference (more toxicity) |
| CALGB 90401 | Bevacizumab | No survival difference (better progression-free survival) |
| READY | Dasatinib | No difference in survival |
| VENICE | Aflibercept | No survival difference (more toxicity) |
Details From the VENICE Trial
The VENICE trial, led by Ian Tannock, MD, PhD, DSc, from the Princess Margaret Cancer Center in Toronto, was conducted in 31 countries. It involved 1224 men with metastatic CRPC who were treated with docetaxel (75 mg/m² intravenously every 3 weeks) and oral prednisone (5 mg twice daily) who were randomized to receive either aflibercept (6 mg/kg) or placebo intravenously every 3 weeks.
In the final analysis, at a median follow-up of 35 months, 873 men had died. The mean overall survival was 22.1 months in the aflibercept group and 21.2 months in the placebo group. This was longer than the 19-month survival that was anticipated for docetaxel and prednisone when the trial was designed, and is "probably longer than would be achieved in general oncologic practice," the study authors note.
The incidence of grade 3/4 gastrointestinal disorders was higher with aflibercept than with placebo (300% vs 8.0%), as was the incidence of hemorrhagic events (5.2% vs 1.7%), hypertension (13.0% vs 3.3%), fatigue (16.0% vs 7.7%), infections (20.0% vs 10.0%), and treatment-related fatal adverse events (3.4% vs 1.5%).
Lesson to Be Learned
Dr. Tannock and colleagues note that the VENICE trial was based on minimal preclinical and early clinical trial data. The decision to rapidly proceed to phase 3 was based on the expectation that antiangiogenic agents would be effective, and that bevacizumab added to docetaxel and prednisone would become the new standard of care.
Several of the other trials were also based on minimal preclinical and early clinical trial data, they add.
"Prostate cancer investigators and sponsors should learn from this experience," Dr. Tannock and colleagues conclude.
"Future clinical trials should proceed only after rigorous preclinical and phase 2 data show substantial preliminary evidence of benefit, and they should be have tighter criteria for early stopping if substantial benefit can be excluded at interim analyses," they write.
The VENICE Trial was funded by Sanofi and Regeneron, the manufacturer of aflibercept. Dr. Tannock reports receiving research funding from Sanofi. Some of his coauthors report acting as consultants for Sanofi, and 2 are company employees, as detailed in the paper. Dr. Galsky reports serving on the advisory board for Dendreon, Astellas, and Janssen. Dr. Oh reports serving on the advisory board for Dendreon, Astellas, Janssen, Pfizer, and sanofi-aventis.
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